PROJECT SUMMARY Feminizing hormone therapy (FHT) for transgender women (TW) modulates inflammatory, metabolic and coagulation pathways and causes fat gain and loss of lean mass, but the degree to which these perturbations translate into altered risk of cardiometabolic disease is not well understood. Additionally, up to 44% of TW are HIV-infected (HIV+). Chronic HIV infection is characterized by persistent inflammation and immune activation that leads to metabolic disturbances, including cardiovascular disease (CVD), that are leading causes of morbidity and mortality in HIV+ adults. It is currently unknown whether FHT exacerbates or ameliorates HIV- associated cardiometabolic disease risk in TW, and data that identify specific immuno-metabolic pathways affected by FHT in HIV+ TW and/or how changes in these pathways translate to clinical disease burden are lacking. The Multicenter AIDS Cohort Study (MACS) is a long-term, observational cohort of HIV+ and HIV-uninfected (HIV-) men who have sex with men. Men enrolled in the MACS CVD2 sub-study have detailed cardiometabolic and inflammatory/metabolic biomarker profiling, and sociodemographic risk factors similar to many TW. In a cross-sectional, pilot study, we will enroll 40 TW 40-70 years of age on FHT, with and without HIV infection. TW will be age-, race-, body mass index- and HIV serostatus-matched (1:2) to HIV+ and HIV- MACS CVD2 control men, and will undergo similar cardiometabolic profiling to MACS CVD2 men (cardiac computed tomography [CT] imaging including coronary angiography for coronary artery calcium scoring, calcified and non-calcified plaque burden, coronary artery stenosis assessment and epicardial and pericardial fat quantification; non-contrast, single slice abdomen and thigh CT for visceral and subcutaneous fat and lean mass quantification; and blood collection for hormone and biomarker profiling). Using these data, we aim to determine in TW on FHT compared to control men: 1) the effects of HIV and FHT use on circulating metabolic, inflammatory and coagulation biomarker levels; 2) the effects of HIV and FHT use on CVD burden; and 3) the effects of HIV and FHT use on central and peripheral fat and lean mass quantity and quality. This novel pilot project will expand understanding of cardiometabolic disease and immuno-metabolic perturbations in TW on FHT, and help optimize care and improve quality of life for TW, a vulnerable and understudied population.